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Calcium antagonists in systemic hypertension: Focus on verapamil concluding remarks part I
CalciumAntagonistsin SystemicHypertension: Focuson Verapamil Concluding RemarksPart I JOHN
H. LARAGH,
W
e have been discussing one of the most important advances in therapeutics, and one that has special relevance to high blood pressure: the use of specific agents to block calcium influx. The past 25 years have revolutionized our knowledge of what high blood pressure is and how to deal with it. We have learned that not all high blood pressure is alike. Those 10% or more of all adults around the world who have an abnormally high blood pressure are not all suffering from the same disorder. This pervades modern thinking, just as the monolithic view pervaded the past. If we recognize that high blood pressure is like fever and that it has many causes, we will now and in the future never recommend a single therapy for all people with high blood pressure. We will instead strive for individualized and rationalized therapies, in which each patient receives the minimal number of drugs at its minimal effective dosage and frequency. In the past 25 years of research this heterogeneity has been defined physiologically and pharmacologically. One of the first things I learned when I started in this field is that often, when a particular drug works well in 1 patient, it may not work at all in another; there is heterogeneity of drug responsiveness. Also we know now, as we knew 50 years ago, that sodium depletion is good treatment for some people with hypertension, but only for about one-third. The other two-thirds can follow a no-salt diet or a rice diet ad infinitum and nothing will happen to their blood pressures. Indeed, if sodium depletion were as effective as some people claim it is, we would not need any drugs. Sodium depletion is an important therapy in some people, but it is not for every person with hypertension. If one accepts the concept of heterogeneity of hypertension and also a key role for dietary sodium in some, From The Cardiovascular Center, New York Hospital, Cornell Medical Center, New York, New York. Address for reprints: John H. Laragh, MD, Cardiovascular Center, New York Hospital, Cornell Medical Center, K400, 525 East 68th Street, New York, New York 10021.
MD
we can build on these tenets. We know a lot about the sodium factor because we know there is a hormonal system, the renin-angiotensin-aldosterone system, that regulates very closely the amount of sodium retained in all of us and in all hypertensive patients, too. We have learned that patients with high blood pressure who have low renin values are the ones who are sodium sensitive and presumably have high blood pressure related to too much sodium somewhere in their bodies. Their very low renin levels strongly suggest that this sodium surfeit has expanded their extracellular space and thereby suppressed their renin. The correction of the blood pressure and renin values by a diuretic confirms this idea. We also know that patients with high renin values are probably sodium depleted and that a low-salt diet or a diuretic will not work for them; in fact, it will have a detrimental effect. Thus, high-renin Goldblatt hypertension is actually worsened by sodium depletion. There has been much resistance to this reasoning, but it appears to be waning. An analogous situation exists with the calcium influx antagonist drugs. Professor Fleckenstein did his monumental work as long as 20 years ago. His discovery of these drugs and his enumeration of the different species of these drugs have taken a very long time indeed to be recognized and appreciated. The blockage of the calcium channel seems to be a more universal point of attack than blockage of the renin system, because some people have renin involved in their hypertension and some do not and this activity is related to sodium metabolism. The calcium channel seems to translate at a distal point the arteriolar vasoconstriction of many forms of hypertension, including the adrenergic-mediated and possibly other mechanisms, but it does not appear to block completely angiotensin-mediated vasoconstriction. It is for this reason that the calcium-channel blocking drugs appear to be effective in such a broad spectrum of patients. In addition to blocking calcium influx in the heart and the arteries, calcium-channel blockade may have another exciting potential as Professor Fleckenstein
aan
A SYMP0SIuM:
CALCIUM
ANTAC~~NISTS
IN HYPERTENS~~N---F~O~S
has proposed. He reminds us that there may be too much calcium in the arteries of all people as they age and that vascular disease in general may have, as a common event, intracellular calcinosis. He also performed experiments to show that the feeding of calcium influx antagonists can prevent the vascular disease in such animal models. This gives us a real assignment in clinical investigation. We must reexamine the whole question of the dietary calcium in humans and we must examine, for the first time, the role of the calcium hormones, parathormone, 1,25-dihydroxy vitamin D and calcitonin, because it is not likely to be the total amount of calcium in the body, any more than the total amount of sodium in the body that is most important. Distribution may be the key issue. Thus, a patient who is calcium depleted in his bones, with marked osteoporosis, may still have too much calcium in his blood vessels. It is in this area of distribution that I believe analysis of the calcium hormone system and perhaps the concurrent role of the renin system has great promise. We have animal models and we have human patients with high blood pressure and the animal models reaffirm that not all hypertension is alike. Even the frequently studied spontaneously hypertensive rat does not resemble human hypertension in many ways, but it does in 1 very powerful way: the low-sodium diet does not work in the spontaneously hypertensive rat. Even a O-salt diet does not lower the pressure in this model. So I believe that we need other animal models of human hypertension. I also believe that the Goldblatt model, which is also independent of dietary sodium, will prove to have more frequent clinical counterparts than we have imagined. Why are the calcium blockers such a major advance? They have been the means of discovering new facts about the physiology of vasoconstriction because vasoconstriction of the arterioles is the fundamental hallmark of all human hypertension. We now can use the calcium-channel blocking drugs to relieve this vasoconstriction when it is largely calcium dependent, just as we can use renin-blocking drugs to relieve it when it is renin-angiotensin-mediated. These 2 types of probes may be useful for identifying and striking 2 different vasoconstriction mechanisms, which partici: pate in different degrees in different patients. Therefore, I believe these 2 therapeutic strategies together provide the most sophisticated and modern approach to the treatment of all hypertension. The clinical translation of this can be stated very simply: When the blood pressure is lowered either with a converting enzyme inhibitor or with a calcium blocker like verapamil, these 2 modes of therapy do something we could not do before. These agents, by themselves, can lower the blood pressure while at the same time improving the flow to the heart, brain, kidneys and muscles. Lowering the blood pressure with a diuretic is like boring a hole in the floor to fix a leak in the ceiling. Everyone who has his blood pressure lowered with a diuretic is volume depleted; it is very easy to demonstrate this. Associated with this volume depletion is exercise intolerance, as are other unwanted effects
ON vERAPAMlL
such as hemoconcentration, azolemia, hyperuricemia, hypokalemia, an abnormal lipid profile and, more recently, clear evidence from large clinical trials that with this type of treatment you do not protect the patient from the major burden of hypertension-associated coronary artery disease. In fact coronary events may even be increased by diuretic-based therapies. There are other problems with long-term diuretic therapy, such as the induction of a diabetic glucose tolerance curve and a significant incidence of impotence. Therefore, we need a better strategy for many patients with hypertension. Another technique that we did not have before that has been mentioned here is calcium-channel blockade. In this regard, I will suggest where I think the calcium-channel blockers as a group fit into modern therapy. Finally, I will suggest why verapamil might be preferred over other types of calcium-channel blocking drugs. Five major types of drugs can be used as primary therapy to treat high blood pressure: diuretics, /3 blockers, (Y blockers, converting enzyme inhibitors and calcium blockers. There will always be a use for diuretic drugs because some persons with high blood pressure have too much sodium in their bodies, so a diuretic is appropriate. However, the role of diuretic drugs appears likely to become much more focused and restricted, and their unselective use will cease. Beta blockers also reduce flow when they lower pressure, but they do have a great theoretical advantage for. treatment because they have been shown in secondary trials to protect the heart from a subsequent myocardial infarction. I believe their use will also become more selective. They are most appropriately used in patients with attendant heart disease as well as in patients with high or medium renin levels. There are many good reasons for lowering renin levels when they are high. The a-blocking drugs, of which there are only a few on the market, lack potency. They will not be discussed as primary drugs here, although they are sometimes effective as monotherapy. The 2 most recently developed agents are the converting enzyme inhibitors and the calcium-channel blockers, Converting enzyme inhibitors must have a primary role in therapy because the cause of hypertension is increased renin secretion. Beyond that, their use in persons with medium renin levels to control inappropriate renin secretion has great promise too, but this issue is controversial. The calcium blockers have a broad spectrum of activity; they are most effective in low renin value patients in whom a sodium excess is involved, but they work well in medium and even sometimes, to a lesser degree as Mtiller has shown, in patients with high renin levels. The calciumchannel blocking drugs, like the converting enzyme inhibitors, increase flow when they lower pressure, so they can be expected not to produce signs of exercise intolerance. The quality of life should be better; there is a very low incidence of such effects as impotence and postural hypotension and they appear to be devoid of major toxicity. Further, there is the attractive added possibility, revised by Fleckenstein’s studies,
February 26, 1986
that calcium influx antagonism therapy may protect us all from vascular disease, but this is still speculative in humans. Why choose verapamil to treat our patients as opposed to all of these other very substantially studied and proved types of drugs? When either verapamil or converting enzyme inhibitors alone lower pressure, flow to the vital organs is improved at the same time, but, unlike the dihydropyridines such as nifedepine, neither reflex tachycardia or reflex adrenergic activity occurs nor is there the possibility of headache or reactive edema. Further, among calcium-channel blockers, verapamil has some very special properties connected with the heart: it reduces contractilitysomewhat, it is a good antiarrhythmic drug for supraventricular tachycardias, and it may be in a class by itself for treating idiopathic hypertrophic cardiomyopathy, be-
THE AMERICAN
JOURNAL
OF CARDIOLOGY
Volume 57
.%x3
cause at least in some patients verapamil has an effect that no other known drugs, including /I blockers, have. Thus, verapamil is a special drug and we have a special responsibility to use it wisely and properly. Hypertension therapy must be based increasingly on physiologic profiles of individual patients, with the first goal to give each patient the right drug to correct the pathophysiologic lesion and the second goal to give him or her a drug that is likely to prevent cardiovascular complications. A third goal is to provide that drug in the lowest possible dose at the lowest frequency possible, using 1 drug instead of 2 and 2 instead of 3 for the longterm commitment wherever possible. Within these guidelines the whole class of calcium-channel blocking drugs will play a large role, in my opinion, and verapamil will be one of these in the vanguard of this movement.
H. LARAGH,
W
e have been discussing one of the most important advances in therapeutics, and one that has special relevance to high blood pressure: the use of specific agents to block calcium influx. The past 25 years have revolutionized our knowledge of what high blood pressure is and how to deal with it. We have learned that not all high blood pressure is alike. Those 10% or more of all adults around the world who have an abnormally high blood pressure are not all suffering from the same disorder. This pervades modern thinking, just as the monolithic view pervaded the past. If we recognize that high blood pressure is like fever and that it has many causes, we will now and in the future never recommend a single therapy for all people with high blood pressure. We will instead strive for individualized and rationalized therapies, in which each patient receives the minimal number of drugs at its minimal effective dosage and frequency. In the past 25 years of research this heterogeneity has been defined physiologically and pharmacologically. One of the first things I learned when I started in this field is that often, when a particular drug works well in 1 patient, it may not work at all in another; there is heterogeneity of drug responsiveness. Also we know now, as we knew 50 years ago, that sodium depletion is good treatment for some people with hypertension, but only for about one-third. The other two-thirds can follow a no-salt diet or a rice diet ad infinitum and nothing will happen to their blood pressures. Indeed, if sodium depletion were as effective as some people claim it is, we would not need any drugs. Sodium depletion is an important therapy in some people, but it is not for every person with hypertension. If one accepts the concept of heterogeneity of hypertension and also a key role for dietary sodium in some, From The Cardiovascular Center, New York Hospital, Cornell Medical Center, New York, New York. Address for reprints: John H. Laragh, MD, Cardiovascular Center, New York Hospital, Cornell Medical Center, K400, 525 East 68th Street, New York, New York 10021.
MD
we can build on these tenets. We know a lot about the sodium factor because we know there is a hormonal system, the renin-angiotensin-aldosterone system, that regulates very closely the amount of sodium retained in all of us and in all hypertensive patients, too. We have learned that patients with high blood pressure who have low renin values are the ones who are sodium sensitive and presumably have high blood pressure related to too much sodium somewhere in their bodies. Their very low renin levels strongly suggest that this sodium surfeit has expanded their extracellular space and thereby suppressed their renin. The correction of the blood pressure and renin values by a diuretic confirms this idea. We also know that patients with high renin values are probably sodium depleted and that a low-salt diet or a diuretic will not work for them; in fact, it will have a detrimental effect. Thus, high-renin Goldblatt hypertension is actually worsened by sodium depletion. There has been much resistance to this reasoning, but it appears to be waning. An analogous situation exists with the calcium influx antagonist drugs. Professor Fleckenstein did his monumental work as long as 20 years ago. His discovery of these drugs and his enumeration of the different species of these drugs have taken a very long time indeed to be recognized and appreciated. The blockage of the calcium channel seems to be a more universal point of attack than blockage of the renin system, because some people have renin involved in their hypertension and some do not and this activity is related to sodium metabolism. The calcium channel seems to translate at a distal point the arteriolar vasoconstriction of many forms of hypertension, including the adrenergic-mediated and possibly other mechanisms, but it does not appear to block completely angiotensin-mediated vasoconstriction. It is for this reason that the calcium-channel blocking drugs appear to be effective in such a broad spectrum of patients. In addition to blocking calcium influx in the heart and the arteries, calcium-channel blockade may have another exciting potential as Professor Fleckenstein
aan
A SYMP0SIuM:
CALCIUM
ANTAC~~NISTS
IN HYPERTENS~~N---F~O~S
has proposed. He reminds us that there may be too much calcium in the arteries of all people as they age and that vascular disease in general may have, as a common event, intracellular calcinosis. He also performed experiments to show that the feeding of calcium influx antagonists can prevent the vascular disease in such animal models. This gives us a real assignment in clinical investigation. We must reexamine the whole question of the dietary calcium in humans and we must examine, for the first time, the role of the calcium hormones, parathormone, 1,25-dihydroxy vitamin D and calcitonin, because it is not likely to be the total amount of calcium in the body, any more than the total amount of sodium in the body that is most important. Distribution may be the key issue. Thus, a patient who is calcium depleted in his bones, with marked osteoporosis, may still have too much calcium in his blood vessels. It is in this area of distribution that I believe analysis of the calcium hormone system and perhaps the concurrent role of the renin system has great promise. We have animal models and we have human patients with high blood pressure and the animal models reaffirm that not all hypertension is alike. Even the frequently studied spontaneously hypertensive rat does not resemble human hypertension in many ways, but it does in 1 very powerful way: the low-sodium diet does not work in the spontaneously hypertensive rat. Even a O-salt diet does not lower the pressure in this model. So I believe that we need other animal models of human hypertension. I also believe that the Goldblatt model, which is also independent of dietary sodium, will prove to have more frequent clinical counterparts than we have imagined. Why are the calcium blockers such a major advance? They have been the means of discovering new facts about the physiology of vasoconstriction because vasoconstriction of the arterioles is the fundamental hallmark of all human hypertension. We now can use the calcium-channel blocking drugs to relieve this vasoconstriction when it is largely calcium dependent, just as we can use renin-blocking drugs to relieve it when it is renin-angiotensin-mediated. These 2 types of probes may be useful for identifying and striking 2 different vasoconstriction mechanisms, which partici: pate in different degrees in different patients. Therefore, I believe these 2 therapeutic strategies together provide the most sophisticated and modern approach to the treatment of all hypertension. The clinical translation of this can be stated very simply: When the blood pressure is lowered either with a converting enzyme inhibitor or with a calcium blocker like verapamil, these 2 modes of therapy do something we could not do before. These agents, by themselves, can lower the blood pressure while at the same time improving the flow to the heart, brain, kidneys and muscles. Lowering the blood pressure with a diuretic is like boring a hole in the floor to fix a leak in the ceiling. Everyone who has his blood pressure lowered with a diuretic is volume depleted; it is very easy to demonstrate this. Associated with this volume depletion is exercise intolerance, as are other unwanted effects
ON vERAPAMlL
such as hemoconcentration, azolemia, hyperuricemia, hypokalemia, an abnormal lipid profile and, more recently, clear evidence from large clinical trials that with this type of treatment you do not protect the patient from the major burden of hypertension-associated coronary artery disease. In fact coronary events may even be increased by diuretic-based therapies. There are other problems with long-term diuretic therapy, such as the induction of a diabetic glucose tolerance curve and a significant incidence of impotence. Therefore, we need a better strategy for many patients with hypertension. Another technique that we did not have before that has been mentioned here is calcium-channel blockade. In this regard, I will suggest where I think the calcium-channel blockers as a group fit into modern therapy. Finally, I will suggest why verapamil might be preferred over other types of calcium-channel blocking drugs. Five major types of drugs can be used as primary therapy to treat high blood pressure: diuretics, /3 blockers, (Y blockers, converting enzyme inhibitors and calcium blockers. There will always be a use for diuretic drugs because some persons with high blood pressure have too much sodium in their bodies, so a diuretic is appropriate. However, the role of diuretic drugs appears likely to become much more focused and restricted, and their unselective use will cease. Beta blockers also reduce flow when they lower pressure, but they do have a great theoretical advantage for. treatment because they have been shown in secondary trials to protect the heart from a subsequent myocardial infarction. I believe their use will also become more selective. They are most appropriately used in patients with attendant heart disease as well as in patients with high or medium renin levels. There are many good reasons for lowering renin levels when they are high. The a-blocking drugs, of which there are only a few on the market, lack potency. They will not be discussed as primary drugs here, although they are sometimes effective as monotherapy. The 2 most recently developed agents are the converting enzyme inhibitors and the calcium-channel blockers, Converting enzyme inhibitors must have a primary role in therapy because the cause of hypertension is increased renin secretion. Beyond that, their use in persons with medium renin levels to control inappropriate renin secretion has great promise too, but this issue is controversial. The calcium blockers have a broad spectrum of activity; they are most effective in low renin value patients in whom a sodium excess is involved, but they work well in medium and even sometimes, to a lesser degree as Mtiller has shown, in patients with high renin levels. The calciumchannel blocking drugs, like the converting enzyme inhibitors, increase flow when they lower pressure, so they can be expected not to produce signs of exercise intolerance. The quality of life should be better; there is a very low incidence of such effects as impotence and postural hypotension and they appear to be devoid of major toxicity. Further, there is the attractive added possibility, revised by Fleckenstein’s studies,
February 26, 1986
that calcium influx antagonism therapy may protect us all from vascular disease, but this is still speculative in humans. Why choose verapamil to treat our patients as opposed to all of these other very substantially studied and proved types of drugs? When either verapamil or converting enzyme inhibitors alone lower pressure, flow to the vital organs is improved at the same time, but, unlike the dihydropyridines such as nifedepine, neither reflex tachycardia or reflex adrenergic activity occurs nor is there the possibility of headache or reactive edema. Further, among calcium-channel blockers, verapamil has some very special properties connected with the heart: it reduces contractilitysomewhat, it is a good antiarrhythmic drug for supraventricular tachycardias, and it may be in a class by itself for treating idiopathic hypertrophic cardiomyopathy, be-
THE AMERICAN
JOURNAL
OF CARDIOLOGY
Volume 57
.%x3
cause at least in some patients verapamil has an effect that no other known drugs, including /I blockers, have. Thus, verapamil is a special drug and we have a special responsibility to use it wisely and properly. Hypertension therapy must be based increasingly on physiologic profiles of individual patients, with the first goal to give each patient the right drug to correct the pathophysiologic lesion and the second goal to give him or her a drug that is likely to prevent cardiovascular complications. A third goal is to provide that drug in the lowest possible dose at the lowest frequency possible, using 1 drug instead of 2 and 2 instead of 3 for the longterm commitment wherever possible. Within these guidelines the whole class of calcium-channel blocking drugs will play a large role, in my opinion, and verapamil will be one of these in the vanguard of this movement.